Very low-dosed solid oral dosage forms for hrt

ABSTRACT

The present invention relates to a very low-dosed dosage form for hormone replacement therapy (HRT). More particularly, the present invention concerns a solid oral dosage form comprising about 0.5 mg estradiol and about 0.25 mg drospirenone, and at least one pharmaceutically acceptable excipient. Despite the very low E2 and DRSP doses it has surprisingly been found that a high proportion of the women suffering from moderate to severe hot flushes actually respond to this treatment. Accordingly, the dosage form of the invention may be used as maintenance HRT or may be used already when HRT is initiated.

FIELD OF THE INVENTION

The present invention relates to a very low-dosed dosage form forhormone replacement therapy (HRT). More particularly, the presentinvention concerns a solid oral dosage form comprising about 0.5 mgestradiol (abbreviated “E2”) and about 0.25 mg drospirenone (abbreviated“DRSP”), and at least one pharmaceutically acceptable excipient. Despitethe very low E2 and DRSP doses it has surprisingly been found that ahigh proportion of the women suffering from moderate to severe hotflushes actually respond to this treatment. Accordingly, the dosage formof the invention may be used as maintenance HRT or may be used alreadywhen HRT is initiated.

BACKGROUND OF THE INVENTION

Estrogens, and in particular E2, have been used for decades for treatingestrogen deficiency symptoms, i.e. vasomotor symptoms. Hot flushes arethe most common and bothersome clinical symptom of menopause, affectingapproximately 75% of postmenopausal women (Sterns et al. Lancet2002;360; 1851-1861). Other menopausal symptoms include mood changes,urogenital changes, sexual dysfunction, and skin changes. The increasein occurrence of hot flushes is linked with the reduction of theendogenous estrogen level that goes along with menopause. Menopausalsymptoms cause discomfort and distress, ranging from tolerable to, attimes, severe enough to affect a woman's quality of life. Also, the lossof endogenous estrogen during menopause accelerates the risk for chronicdiseases, such as osteoporosis (Slemenda et al. Epidemiology ofOsteoporisis. In: Treatment of the Postmenopausal Woman Basic andClinical Aspects. Raven Press. New York. 1994, p. 161-168). Currently,there are more than 40 million menopausal women in the United States andalmost half of them are above the age of 63 (Warren et al. Clin ObstetGynecol 2004;47(2);450-470). As life expectancy continues to increase,most women will spend one-third of their lifetime in postmenopause.

Although E2 doses are adjusted during therapy according to individualresponses, it is, needless to say, of importance to establish the lowestE2 dose that confidentially can be used to initiate or maintain therapy.

Important factors, which are relevant in identifying the lowest initialdose of E2, include rapid and adequate release of vasomotor symptoms,and appropriateness for most women. Besides being effective, the initialdose or the maintenance dose should be well tolerated.

Notelovitz et al. (Obstet Gynecol 2000;95(5);726-731) evaluated a rangeof E2 doses for symptom relief in menopausal women who needed treatmentfor moderate and severe vasomotor symptoms, and used the collected datato identify the ideal lowest initial dose. More particular, Notelovitzet al. conducted a randomized, double-masked, placebo-controlled 12-weekstudy in which 333 menopausal women with moderate or severe but flusheswere assigned to treatment with 0.25 mg E2, 0.5 mg E2, 1 mg E2, 2 mg E2,or placebo (administered orally). The number and severity of hot flusheswere recorded on a daily basis.

Notelovitz et al. found a significant linear dose-response relationshipbetween the E2 dose and reduction in vasomotor symptoms, assessed by thenumber of moderate to severe hot flushes and the hot flush weeklyweighted score. At the end of the 12-week treatment period, decreases inthe number of hot flushes and the hot flush weekly weighted score weresignificantly greater in the 0.5-, 1-, and 2-mg groups compared with theplacebo group. However, at week 4 only the 1- and 2-mg groups showedsignificance compared to the placebo group.

Accordingly, Notelovitz et al. concluded that 1 mg E2 is the most usefulstarting dose for treating moderate to severe menopausal symptoms inmenopausal women. According to Notelovitz et al. lower doses eitherrequire more time (0.5 mg E2) or are ineffective (0.25 mg E2) forsymptom relief in women who suffer from moderate to severe vasomotorsymptoms. Conversely, a higher dose of 2 mg E2 is effective for symptomrelief, but is associated with increased estrogen-related adverseevents.

Nevertheless, and as also emphasized by the Women's Health Initiative(WHI), there is still a need for developing and investigating dosageforms having lower doses of E2 for the treatment of vasomotor symptoms.In particular, there is a need for developing dosage forms having lowerdoses of E2 for the treatment of vasomotor symptoms, which have a fastand reliable onset, and hence are suitable to be used already whenhormone replacement therapy is initiated, thereby avoiding initialtreatment with dosage forms containing higher doses of E2.

This is also emphasised in the FDA guidelines where sponsors areencouraged to investigate dosing schedules and drug delivery systemsthat can achieve efficacy with the lowest possible exposures (Guidancefor Industry: Estrogen and Estrogen/Progestin Drug Products to TreatVasomotor Symptoms and Vulvar and Vaginal AtrophySymptoms—Recommendations for Clinical Evaluation; U.S. Department ofHealth and Human Services; Food and Drug Administration; CDER; January2003).

Dosage forms comprising a combination of E2 and DRSP have been describedin WO 01/52857. While low-dose E2 dosage forms are formally encompassedby the disclosure in WO 01/52857, the preferred E2 dose describedtherein is 1 mg.

Low-dose E2-only dosage forms are described in WO 2006/048261.

An HRT product, Angeliq®, which contains 1 mg E2 and 0.5 mg DRSP, hasbeen approved and marketed in the US.

SUMMARY OF THE INVENTION

The present inventor has now surprisingly found that an E2 dosepreviously believed to be too low, is effective in providing a rapid andadequate relief of moderate to severe vasomotor symptoms if such a lowE2 dose is combined with a low dose of DRSP. As will be apparent fromthe examples provided herein, it has surprisingly been found that a highproportion of women suffering from moderate to severe hot flushesresponded to treatment with a solid oral dosage form comprising a lowdose of E2 (about 0.5 mg), when combined with a low dose of DRSP (about0.25 mg).

Accordingly, such dosage forms effectively provide adequate relief ofmoderate to severe vasomotor symptoms, in particular moderate to severehot flushes, in postmenopausal women already within the first few weeksof treatment. Such a low-dosed dosage form can thus be used to initiatehormone replacement therapy or, alternatively, as maintenance therapy.Furthermore, the very low-dosed dosage forms of the invention improvesthe bleeding behavior, in particular it lowers the frequency ofbreakthrough bleedings (increases the incidence rate of amenorrhea).

Accordingly, in a first aspect, the present invention relates to a solidoral dosage form comprising about 0.5 mg E2 and about 0.25 mg DRSP, andat least one pharmaceutically acceptable excipient.

In a second aspect, the present invention relates to a packaging unitconsisting of a number of separately packaged and individually removablesolid oral dosage forms according to the invention, and intended fororal administration for a period of at least 21 days.

In a further aspect, the present invention relates to a solid oraldosage form according to the invention for use as a medicament.

In a still further aspect, the present invention relates to a solid oraldosage form according to the invention for the prevention, treatment oralleviation of vasomotor symptoms in a woman.

In another aspect, the present invention relates to a solid oral dosageform according to the invention for lowering the frequency ofbreakthrough bleedings, or increasing the incidence rate of amenorrhea,in a woman.

In still another aspect, the present invention relates to a method forpreventing, treating or alleviating vasomotor symptoms in a woman, saidmethod comprising administering a solid oral dosage form according tothe invention to a woman in need thereof.

In yet another aspect, the present invention relates to a method forlowering the frequency of breakthrough bleedings, or increasing theincidence rate of amenorrhea, in a woman, said method comprisingadministering a dosage form according to the invention to a woman inneed thereof.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is directed to an oral solid dosage formcomprising about 0.5 mg E2 and about 0.25 mg DRSP, and at least onepharmaceutically acceptable excipient.

As indicated supra the number of patients who responded to this low-dosetherapy turned out to be surprisingly high.

As it appears from the examples provided herein three patient groupswere investigated; a Placebo Group, a 1^(st) Treatment Group receiving0.3 mg E2 (without DRSP), and a 2^(nd) Treatment Group receiving 0.5 mgE2 in combination with 0.25 mg DRSP. As is abundantly clear from thedata shown in the examples, the number of responders in the 2^(nd)Treatment Group was significantly higher than the number of respondersin the 1^(st) Treatment Group as well as in the Placebo Group. In fact,the proportion of subjects who were responders in the 2^(nd) TreatmentGroup was as high as 62.7%.

Due to the increasing E2 (and DRSP) dose in the 2^(nd) Treatment Groupas compared to the 1^(st) Treatment Group and the Placebo Group, thehigher number of responders in the 2^(nd) Treatment Group relative tothe number of responders in the 1^(st) Treatment Group and the PlaceboGroup may not appear surprising per se. What is, however, surprising isthe number of responders in the 2^(nd) Treatment Group when compared toAngeliq® which contains a dose of E2 and DRSP that is twice as high asthe E2 and DRSP doses in the dosage forms of the invention.

Since it is well-known that the numbers of responders receiving HRT withthe Angeliq® preparation is high it is surprising that when the dose ofE2 and DRSP is lowered by 50% (compared to the doses of E2 and DRSP inthe Angeliq® preparation), the number of responders does not drop below50%. In fact, and as already indicated above, the proportion of subjectswho were responders in the 2^(nd) Treatment Group was as high as 62.7%.

Accordingly, a synergistic effect appears to be present between E2 in adose of about 0.5 mg in combination with a dose of DRSP of about 0.25 mgwhen compared to a similar dosage form containing twice the dose of bothactive substances.

In addition, a common problem associated with administration ofcontinues HRT products, such as Angeliq®, is the occurrence ofbreakthrough bleedings. The present inventors have found that the verylow-dosed dosage forms of the invention give rise to fewer breakthroughbleedings in women, in particular postmenopausal women, as compared toHRT products containing a higher E2 dose.

When used herein the term “responder” is defined as a women whoexperiences a reduction (relative to baseline) of 2.7 moderate to severehot flushes per day at week 4, and a reduction (relative to baseline) of5.8 moderate to severe hot flushes per day at week 12.

Herein, the term “E2” (or “estradiol”) is intended to mean that the E2may be in the form of 17-α-E2 or 17-13-E2. Preferably, the E2 is in theform of 17-13-E2. The term “E2” (or “estradiol”) also covers hydratedforms of E2, in particular E2 hemihydrate. It should be understood thatall E2 doses mentioned herein refer to anhydrous E2. Thus, if a hydrateof E2, such as E2 hemihydrate, is employed it will be understood that adose which is equimolar to the stated dose of anhydrous E2 should beused. By way of example, it can easily be calculated that a dose of 0.5mg of anhydrous E2 corresponds to a dose of 0.5×1.033 mg=0.52 mg of E2hemihydrate. The term “E2” (or “estradiol”) also encompassespharmaceutically acceptable esters of E2, such as E2 benzoate or E2valerate, In particular E2 valerate.

The term “about 0.5 mg E2” is intended to mean that a dose slightlylower or higher than 0.5 mg may also be employed, such as an E2 dose inthe range of from 0.45-0.55 mg, e.g. 0.48-0.52 mg. Specific examples ofE2 doses include 0.45 mg, 0.46 mg, 0.47 mg, 0.48 mg, 0.49 mg, 0.50 mg,0.51 mg, 0.52 mg, 0.53 mg, 0.54 mg, and 0.55 mg. The preferred E2 doseis 0.50 mg. As will be understood, similar slightly lower or higherdoses of E2 hemihydrate and pharmaceutically acceptable esters of E2 maybe employed.

Likewise, the term “about 0.25 mg DRSP” is intended to mean that a doseslightly lower or higher than 0.25 mg may also be employed, such as aDRSP dose in the range of from 0.20-0.30 mg, e.g. 0.23-0.27 mg. Specificexamples of E2 doses include 0.20 mg, 0.21 mg, 0.22 mg, 0.23 mg, 0.24mg, 0.25 mg, 0.26 mg, 0.27 mg, 0.28 mg, 0.29 mg, and 0.30 mg. Thepreferred DRSP dose is 0.25 mg.

DRSP, which is a progestin with anti-aldosterone activity, has beendeveloped for HRT in combination with E2, and constitutes part of thecommercially available HRT product, Angeliq®, cf. supra. DRSP isfurthermore characterised by a pharmacological profile which is moreclosely related to that of endogenous progesterone than that of othersynthetic progestins in use today. The main reason for incorporatingDRSP in HRT products is that DRSP protects the endometrium from adverseeffects of the E2.

Vasomotor symptoms comprise, but are not limited to hot flushes,sweating attacks such as night sweats, and palpitations. The vasomotorsymptoms may be “mild”, “moderate” or “severe” as defined by the FDAguidelines (cited supra). Thus, in the present context, the term “mildvasomotor symptoms” is defined as “sensation of heat without sweating”;the term “moderate vasomotor symptoms” is defined as “sensation of heatwith sweating, but able to continue activity”; and the term “severevasomotor symptoms” is defined as “sensation of heat with sweating,causing cessation of activity”.

Psychological symptoms of estrogen deficiency comprise, but are notlimited to, insomnia and other sleep conditions, poor memory, loss ofconfidence, mood changes, anxiety, loss of libido, difficulties inconcentration, difficulty in making decisions, diminished energy anddrive, irritability and crying spells. The treatment or alleviation ofthe aforementioned symptoms can be associated with the perimenopausalphase of a woman's life or after, sometimes long time after, menopause.It is anticipated that the dosage form of the invention is alsoapplicable to these and other transient symptoms during theperimenopausal phase, menopause, or postmenopausal phase. Moreover, theaforementioned symptoms can be alleviated if the cause of the estrogendeficiency is hypogonadism, castration or primary ovarian failure. Inanother embodiment of the invention, the dosage form of the invention isused for the prevention, treatment or alleviation of permanent effectsof estrogen deficiency. Permanent effects comprise physical changes suchas urogenital atrophy, atrophy of the breasts, cardiovascular disease,changes in hair distribution, thickness of hair, changes in skincondition and osteoporosis. Urogenital atrophy, and conditionsassociated with it such as vaginal dryness, increase in vaginal pH andsubsequent changes in flora, or events which lead to such atrophy, suchas decreases in vascularity, fragmentation of elastic fibres, fusion ofcollagen fibres, or decreases in cell volume, are symptoms thought to beparticularly relevant to be prevented, treated or alleviated with thedosage form of the invention. Furthermore, the dosage form of theinvention is thought to be relevant to other urogenital changesassociated with estrogen deficiency, decreases in mucus production,changes in cell population, decreases in glycogen production, decreasesin growth of lactobacilli or increases in growth of streptococci,staphylococci, or coliform bacilli. Other associated changes that arepreventable or treatable by administration of the dosage form of theinvention are those that may render the vagina susceptible to injury orinfection, such as exudative discharges, vaginitis, and dyspareunia.

Furthermore, infections of the urinary tract and incontinence are othercommon symptoms associated with lowered estrogen levels. Otherembodiments of the invention include the prevention, treatment oralleviation of physical changes associated with estrogen deficiency,such as changes in the skin, changes in hair distribution, thickness ofhair, atrophy of the breasts, or osteoporosis. Furthermore, bonedemineralisation, reduction of bone mass and density, thinning andinterruption of trabeculae, and/or consequent increase in bone fracturesor bone deformations are thought to be particularly relevant. Theprophylactic treatment of osteoporosis is an interesting therapeuticapplication of the dosage form of the invention. A particularlyinteresting embodiment of the invention is directed to lessening thefrequency, persistence, duration and/or severity of hot flushes (inparticular moderate to severe hot flushes), sweating attacks,palpitations, sleep conditions, mood changes, nervousness, anxiety, poormemory, loss of confidence, loss of libido, poor concentration,diminished energy, diminished drive, irritability, urogenital atrophy,atrophy of the breasts, cardiovascular disease, changes in hairdistribution, thickness of hair, changes in skin condition andosteoporosis (including prevention of osteoporosis), most notably hotflushes, sweating attacks, palpitations, sleep conditions, mood changes,nervousness, anxiety, urogenital atrophy, atrophy of the breasts, aswell as prevention or management of osteoporosis. Another interestingembodiment of the invention is directed to prevention, treatment oralleviation of hot flushes, sweating attacks, palpitations, sleepconditions, mood changes, nervousness, anxiety, poor memory, loss ofconfidence, loss of libido, poor concentration, diminished energy,diminished drive, irritability, urogenital atrophy, atrophy of thebreasts, cardiovascular disease, changes in hair distribution, thicknessof hair, changes in skin condition and osteoporosis (includingprevention of osteoporosis), most notably hot flushes, sweating attacks,palpitations, sleep conditions, mood changes, nervousness, anxiety,urogenital atrophy, atrophy of the breasts, as well as prevention ormanagement of osteoporosis.

As will be understood, the dosage form of the invention is suitable tobe used already as the initial treatment of the above-mentionedconditions, in particular for the prevention, treatment or alleviationof moderate to severe vasomotor symptoms, such as hot flushes.Alternatively, the dosage form of the invention may be used asmaintenance therapy, i.e. women suffering from vasomotor symptoms may,after initial treatment with a higher-dosed HRT product, such asAngeliq©, switch down to the HRT product described herein.

In a preferred embodiment, the woman to be treated according to theinvention is a postmenopausal woman.

The terms “perimenopause”, “menopause” and “postmenopause” are used intheir conventional meaning, e.g. as defined in Section A of “MenopausePractice: A Clinicians's Guide”, 3^(rd) Edition, 2007, The NorthAmerican Menopause Society (NAMS). More particularly, the term“menopause” is understood as the last natural (ovary-induced)menstruation. It is a single event and a result of an age-dependentdysfunction of the ovarian follicles. Menopause results from the ovariesdecreasing their production of the sex hormones estrogen andprogesterone. When the number of follicles falls below a certainthreshold, the ovaries can no longer produce mature follicles and sexhormones. The ability to reproduce ends with menopause. Theperimenopausal phase begins with the onset of climacteric symptoms whenthe cycle becomes irregular and ends one year after menopause. The endof perimenopausal phase can be identified after a protracted period oftime without bleeding. Postmenopause is the phase that begins atmenopause and continues until death.

The woman to be treated according to the invention may be ahysterectomised or non-hysterectomised woman. In an interestingembodiment of the invention, the woman to be treated according to theinvention is a non-hysterectomised woman, in particular anon-hysterectomised postmenopausal woman.

Hysterectomy is the surgical removal of the uterus. A total hysterectomyis removal of the uterus and cervix. A partial hysterectomy is removalof the uterus leaving the stump of the cervix (also calledsupra-cervical). Hysterectomy can be accompanied by surgical removal ofthe ovaries (oophorectomy). Removal of the female gonads, the ovaries,is female castration. Women who undergo total hysterectomy withbilateral salpingo-oophorectomy (removal of both ovaries, i.e.castration) lose most of their hormone production, including manyestrogens and progestins. A woman who is undergoing natural menopausehas intact and functional female organs, while a woman who has beenhysterectomised and castrated does not. Accordingly, in the presentcontext the term “hysterectomised woman” refers to a woman who hasundergone total or partly hysterectomy, and a “non-hysterectomisedwoman” refers to a woman who has not undergone total or partlyhysterectomy.

As discussed supra, the dosage form of the invention is suitable to beused already as the initial treatment of the above-mentioned conditions,in particular for the prevention, treatment or alleviation of moderateto severe vasomotor symptoms, such as hot flushes. Accordingly, in aninteresting embodiment, the dosage form of the invention is administeredto a woman who has not previously received estrogen therapy, or who isnot currently receiving estrogen therapy. In another interestingembodiment of the invention, the dosage form of the invention isadministered to a woman who has previously received estrogen therapy, oris currently receiving estrogen therapy, in particular estrogen therapywhere the administered daily dose of E2 is >0.5 mg.

In the present context, the term “oral solid dosage form” generallyrefers to tablets (both swallowable-only and chewable forms), capsules,granules, granules enclosed in sachets and pills. Hence, the dosage formof the invention may be in the form of a tablet, capsule, gelcap,granule, sachet or a pill. In a preferred embodiment of the invention,the dosage form is in the form of a tablet or a capsule, in particularin the form of a tablet.

The dosage form of the invention is preferably provided in the form ofan immediate release dosage form. When used herein, the term “immediaterelease” means that at least 70% of at least one, but preferably both,of the active ingredients are dissolved within 30 minutes when subjectedto dissolution testing in 900 ml water, or 900 ml 0.1N HCl, at 37° C.using USP XXIII Paddle Method II operated at a stirring rate of 50 rpm.In a preferred embodiment, at least 80% of the at least one, butpreferably both, active ingredients are dissolved within 30 minutes whensubjected to dissolution testing as described above. In an even morepreferred embodiment, at least 90% of the at least one, but preferablyboth, active ingredients are dissolved within 30 minutes when subjectedto dissolution testing as described above.

Preparation of immediate release dosage forms is well-known to theskilled person. A general description of various factors influencing thedissolution properties are described in, e.g., Remington'sPharmaceutical Sciences, 18^(th) Edition, 1990, Chapter 31, page591-595. For example, immediate release dosage forms may be prepared byproviding the active ingredient(s) in micronized form, such as describedin WO 01/52857. Alternatively, the active ingredient(s) may be depositedon the surface of inert carrier particles, e.g. by dissolving the activeingredient(s) in a suitable organic solvent and then spraying the activeingredient(s) onto the surface of said inert carrier particles, such asdescribed in WO 01/52857. As a further alternative, immediate releasedosage forms may be prepared by incorporating dissolution-promotingexcipients in the dosage form, such as described in WO 01/52857.Preferred dissolution-promoting excipients are surfactants, such asthose mentioned from page 5, line 5, to page 7, line 4, of WO2006/128907. Among these surfactants the so-called polysorbates arepreferred, in particular polysorbate 80. As will be known to the skilledperson, the polysorbates are commercially available under the trademarkTween®. As a still further alternative, immediate release dosage formsmay be prepared by providing the active ingredient(s) in amorphous form,such as described in WO 2009/138224.

When used herein, the term “micronized” means that the activeingredient(s) has the following particle size distribution, asdetermined by laser diffraction: 90% of the particles have a diameter of≦20 μm, and 50% of the particles have a diameter of ≦10 μm, preferably≦5 μm. It should be understood that the term “micronized” also meansthat the particle size distribution, as determined by laser diffraction,is such that 90% of the particles have a diameter greater than 0.1 μm,preferably greater than 0.2 μm. The determination of particle size bylaser diffraction may be carried out using Sympatec HELIOS, (dispersion)operated with a pressure of 1-4 bar.

As mentioned above, the dosage form of the invention preferably exhibitsimmediate release of the active ingredient(s). This, in turn, means thatthe disintegration time of the dosage form preferably is short in orderto enable rapid release of the active ingredient(s). The disintegrationtime should preferably be less than 10 minutes, more preferably lessthan 5 minutes, as determined according to the United StatesPharmacopoeia (USP 27; chapter <701>) without using a disc. In an evenmore preferred embodiment, the disintegration time is less than 4minutes, such as less than 3 minutes, e.g. less than 2 minutes.

By the term “bioavailability” is meant the amount of DRSP or E2, thathas been absorbed into the circulating blood following oraladministration and is often determined relative to the amount present inthe circulating blood following intravenous (i.v.) administration of asimilar amount of the same active ingredient. The bioavailability may bedetermined as the ratio AUC_(0-24h) (oral administration)/AUC_(0-24h)(i.v. administration).

As described in e.g. WO 2006/048261, a dosage form containing a low doseof E2 may become chemically unstable in the presence of excipients,which have decomposing, such as oxidising, potentials greater than orsimilar to polyvinylpyrrolidone (PVP). Accordingly, it is preferred thatthe amount of such excipients is not too high in the dosage form of theinvention. Therefore, an interesting embodiment of the inventionencompasses a dosage form in which the weighed ratio between PVP and E2is 10:1 or less. In absolute numbers, the dosage form of the inventionpreferably contains less than 5 mg PVP, such as about 4 mg PVP.

By the term “polyvinylpyrrolidone” (or “PVP”) is meant a syntheticpolymer having the empirical formula (C₆H₉NO)_(n) and a molecular weightranging from 2,500 to 3,000,000 and which consists essentially of linear1-vinyl-2-pyrrolidone groups. Obviously, other excipients having thesame oxidising power as PVP with respect to E2 is preferably to beexcluded or used in limited amounts in the dosage form of the invention.An example of such other excipient may be Crospovidone. When used in ansolid oral dosage form, PVP has a diversity of functions, such as actingas a disintegrant, as a dissolution aid (solubiliser, improvement of thewettability), as a suspending agent and as a tablet binder. PVP is, inparticular, used in connection with highly hydrophobic drugs so as toovercome the critical step of solubilising the active drug in thegastric fluid before the actual dissolution can take place.

In order to improve the chemical stability of the active ingredient(s)present in the dosage form of the invention, but in particular E2, maybe complexed with a cyclodextrin.

The term “E2-cyclodextrin complex” or “E2 complexed with cyclodextrin”is intended to mean a complex between E2 and a cyclodextrin, wherein theE2 molecule is at least partially inserted into the cavity of acyclodextrin molecule. The molar ratio between E2 and the cyclodextrinmay be adjusted to any desirable value. In interesting embodiments ofthe invention, a molar ratio between E2 and the cyclodextrin is fromabout 2:1 to 1:10, preferably from about 1:1 to 1:5, most preferablyfrom about 1:1 to 1:3, such as 1:1 or 1:2, in particular 1:2.Furthermore, the E2 molecule may at least partially be inserted into thecavity of two or more cyclodextrin molecules, e.g. a single E2 moleculemay be inserted into two cyclodextrin molecules to give 1:2 ratiobetween E2 and the cyclodextrin. Similarly, the complex may contain morethan one E2 molecule at least partially inserted into a singlecyclodextrin molecule, e.g. two E2 molecules may be at least partiallyinserted into a single cyclodextrin molecule to give a 2:1 ratio betweenE2 and cyclodextrin. Complexes between E2 and cyclodextrins may beobtained by methods known in the art, e.g. as described in U.S. Pat. No.5,798,338 and EP 1 353 700.

The term “DRSP-cyclodextrin complex” or “DRSP complexed withcyclodextrin” is intended to mean a complex between DRSP and acyclodextrin, wherein the DRSP molecule is at least partially insertedinto the cavity of a cyclodextrin molecule. The molar ratio between DRSPand the cyclodextrin may be adjusted to any desirable value. Ininteresting embodiments of the invention, a molar ratio between DRSP andthe cyclodextrin is from about 2:1 to 1:10, preferably from about 1:1 to1:5, most preferably from about 1:1 to 1:3, in particular 1:3.Furthermore, the DRSP molecule may at least partially be inserted intothe cavity of two or more cyclodextrin molecules, e.g. a single DRSPmolecule may be inserted into two cyclodextrin molecules to give 1:2 or1:3 ratio between DRSP and cyclodextrin. Similarly, the complex maycontain more than one DRSP molecule at least partially inserted into asingle cyclodextrin molecule, e.g. two DRSP molecules may be at leastpartially inserted into a single cyclodextrin molecule to give a 2:1ratio between DRSP and cyclodextrin. Complexes between DRSP andcyclodextrins may be obtained by methods known in the art, e.g. asdescribed in U.S. Pat. No. 6,610,670 and references therein.

The term “cyclodextrin” is intended to mean a cyclodextrin or aderivative thereof as well as mixtures of various cyclodextrins,mixtures of various derivatives of cyclodextrins and mixtures of variouscyclodextrins and their derivatives. The cyclodextrin may be selectedfrom the group consisting of α-cyclodextrin, β-cyclodextrin,γ-cyclodextrin and derivatives thereof. β-cyclodextrin is particularlypreferred. The cyclodextrin may be modified such that some or all of theprimary or secondary hydroxyl groups of the macrocycle are alkylated oracylated. Methods of modifying these hydroxyl groups are well known tothe person skilled in the art and many such modified cyclodextrins arecommercially available. Thus, some or all of the hydroxyl groups of thecyclodextrin may have been substituted with an O—R group or an O—C(O)—Rgroup, wherein R is an optionally substituted C₁₋₆-alkyl, an optionallysubstituted C₂₋₆-alkenyl, an optionally substituted C₂₋₆ ⁻alkynyl, anoptionally substituted aryl or heteroaryl group. Thus, R may be amethyl, an ethyl, a propyl, a butyl, a pentyl, or a hexyl group, i.e.O—C(O)—R may be an acetate. Furthermore, the hydroxyl groups may beper-benzylated, per-benzoylated, benzylated or benzoylated on just oneface of the macrocycle, i.e. only 1, 2, 3, 4, 5 or 6 hydroxyl groupsis/are benzylated or benzoylated. Naturally, the hydroxyl groups mayalso be per-alkylated or per-acylated, such as per-methylated orper-acetylated, alkylated or acylated, such as methylated or acetylated,on just one face of the macrocycle, i.e. only 1, 2, 3, 4, 5 or 6hydroxyl groups is/are alkylated or acylated, such as methylated oracetylated. Commonly used cyclodextrins arehydroxypropyl-β-cyclodextrin, DIMEB, RAMEB and sulfoalkyl ethercyclodextrins, such as sulfobutyl ether cyclodextrin (available underthe trademark Captisol®. Although cyclodextrin-complexed activeingredients are indeed contemplated, the dosage form, in one embodimentof the invention, does not contain any cyclodextrin.

In the present context, the term “C₁₋₆-alkyl” is intended to mean alinear or branched saturated hydrocarbon chain having from one to sixcarbon atoms, such as methyl; ethyl; propyl, such as n-propyl andisopropyl; butyl, such as n-butyl, isobutyl, sec-butyl and tert-butyl;pentyl, such as n-pentyl, isopentyl and neopentyl; and hexyl, such asn-hexyl and isohexyl. Likewise, the term “C₁₋₄ ⁻alkyl” is intended tomean a linear or branched saturated hydrocarbon chain having from one tofour carbon atoms, such as methyl; ethyl; propyl, such as n-propyl andisopropyl; and butyl, such as n-butyl, isobutyl, sec-butyl andtert-butyl.

Although various cyclodextrin complexes of DRSP and E2 are describedabove, it is currently preferred that neither DRSP, nor E2, is complexedwith a cyclodextrin. Accordingly, in a preferred embodiment, the dosageform of the invention does not contain a cyclodextrin.

The term “binder”, as used herein, is generally meant to describe anagent that imparts cohesive qualities to the powdered material(s), thuslinking primary particles of powdered materials to secondary aggregates.When manufacturing tablets using a process implying directly compressinga powdery mixture of the active ingredient into tablets, a binder isadded to the powder mixture so as to increase the cohesion within thetablet during the compression steps. Accordingly, the binder is said tobe included in the “external phase”. Conversely, when manufacturingdosage forms wherein the active ingredient is combined with excipientsin a granulate, i.e., wherein the manufacturing process implies agranulation step, the binder may be added to the granulation mixture soas to stabilise the resulting granules. Then, the binder is said to bepresent in the “internal phase”. The binder may also be added aftercompletion of the granulation step, which relate to the binder in the“external phase”. Thus, it is to be understood that the term “internalphase” refers to the composition inside the granules and the term“external phase” refers to the composition outside the granules. In someinteresting embodiments of the invention, the binder is preferably inthe “internal phase”. When wishing to have the binder in the “internalphase”, the skilled artisan knows that the binder can optionally beadded as a dry powder to the mixture of powdered materials. Anotheroption is to dissolve or suspend the binder in water or any othersuitable solvent or mixture of solvents including aqueous solutions,which is then used as granulation liquid. Still another option is to addthe binder partly as a dry powder to the powder mixture and partly indissolved or suspended form via the granulation liquid.

The term “first choice binder” encompasses a binder that act as a binder(in dry as well as in wetted, swelled and dissolved form) and which alsohas solubilising properties. PVP is the sole example of such a binder.The term “second choice binder” encompasses binders that act as abinder, in dry, wetted, swelled or dissolved form in the preparation ofan oral dosage form. They are characterised by lacking or having limitedwettability properties. That is to say that upon contacting an estrogen,such as E2, with a media (such as an aqueous solution) comprising a“second choice binder”, the contact angle between the media and theestrogen is not effectively decreased or is not decreased at all.Furthermore, such a binder does normally not increase the dissolutionrate of the active ingredient(s). Commonly used binders include acacia;alginic acid; alkali metal alginate; carbomer; dextrin; dicalciumphosphate; gelatin; glucose; guar gum; hydrogenated vegetable oil;magnesium aluminium silicate; spray-congealed mannitol; zein; starch,such as maize starch, potato starch, rice starch, tapioca starch orwheat starch; partly or fully modified or pregelatinized starch; starchderivatives, such as maltodextrin; partly or fully modified orpregelatinized starch; cellulose, such as microcrystalline cellulose;cellulose derivatives, such as carboxymethylcellulose, ethyl cellulose,hydroxypropyl cellulose, hydroxyethyl-methyl cellulose,hydroxypropylmethyl cellulose and methylcellulose; and mixtures thereof.

By “starch” is generally meant a substance having the empirical formula(C₆H₁₀O₅)_(n), where n is 300-1000 and the molecular weight is of50,000-160,000 and which consists of amylose and amylopectin, that areboth polysaccharides based on α-glucose units. Starch is derived fromplant materials, and is commonly found in the form of tiny microscopicgranules (5-25 microns in diameter) comprised of stratified layers ofstarch molecules formed around a hilum nucleus. The starch granule maybe round, oval or angular in shape, and consists of a radially orientedcrystalline aggregate of two anhydrous D-glucose polymers: Amylose andamylopectin. The former is a straight chain polymer of several hundredglucose units linked by alpha-1-4-glycosidic linkages. Amylopectin is abranched polymer of several thousand glucose units withalpha-1-6-glycosidic linkages at the branched points and alpha-1-4linkages in the linear regions. Individual branches may have between20-30 glucose residues.

In specific embodiments of the invention the starch is selected from thestarches that have a content of amylose in the range of 10% and 40% byweight. Typical examples are maize starch, potato starch, rice starch,tapioca starch and wheat starch.

In one embodiment of the invention, starch is used as a binder in aconcentration of 1-5% by weight of the dosage form, preferably in therange of 2-3% by weight. The starch may be used in swelled, suspended ordissolved form in a granulation liquid or in the form of dry powder.Starch may be used in its unmodified, modified as well as partiallymodified form. When used herein for the purpose of granulating a powderymixture of DRSP, E2 and at least one pharmaceutically acceptableexcipient, the starch is preferably in the unmodified form. The totalamount of starch may, however, be significantly higher than indicatedabove, e.g. in the range of 5-25% by weight of the dosage form.

The terms “modified starch” and “pregelatinized starch” areinterchangeable terms and are meant to define starch that has beenchemically and/or mechanically processed to rupture all or part of thegranules in the presence of water and subsequently dried. Some types ofpregelatinized starch may be modified to render them improvedcompressibility and flowability character. Typically pregelatinizedstarch contains 5% of free amylose, 15% of free amylopectin and 80%unmodified starch. Pregelatinized starch may be maize starch that isprocessed in the above-described chemical and/or mechanical manner.Other types of starch than maize starch may be pregelatinized, such asrice or potato starch.

The terms “partially modified starch” and “pregelatinized starch” areinterchangeable terms and are meant to define a pregelatinized starchthat is modified to a lower extent than pregelatinized starch.Pharmaceutical grades of fully pregelatinized starch use no additivesand are prepared by spreading an aqueous suspension of ungelatinizedstarch on hot drums where gelatinization and subsequent drying takesplace. Subjecting moistened starch to mechanical pressure producespartially pregelatinized starch.

The term “unmodified starch” is meant to define unprocessed starch asdefined under the term “starch” above.

The term “cellulose derivatives” is meant to encompass cellulose inwhich a portion, or all, of the free hydroxy groups have been replacedby ether- and/or ester groups. Thus, a cellulose derivative is acellulose ester and/or a cellulose ether. The ether or ester groups mayhave various carbon chain lengths such as chains with up to 10 carbonatoms, preferably up to 8, 6, 5, or 4 carbon atoms. Typical examples oncellulose derivatives are the carboxymethyl cellulose sodium,ethylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose,methylcellulose. Interesting binders are the low-substituted cellulosederivatives, especially hydroxypropyl methylcellulose and hydroxypropylcellulose. The term “low-substituted” indicates that not less than 5%and not more than 16% of the hydroxyl groups have been replaced by anether and/or ester group. The cellulose derivatives may be selectedaccording to their resulting viscosity in a 2% aqueous solution.Typically, cellulose derivatives suitable as binders exhibit a resultingviscosity range in a 2% aqueous solution of 1-20 mPas, preferably of2-12 mPas, most preferably of about 3-6 mPas. The cellulose derivativeis typically used in a concentration of concentration of 0.5-5% byweight of the dosage form.

In an interesting embodiment of the invention, hydroxypropyl cellulose,such as low-substituted hydroxypropyl cellulose, is used in aconcentration of 0.5-5% by weight of the dosage form, preferably in therange of 1-3% by weight.

In a preferred embodiment of the invention, the binder is present in theso-called “internal phase” of a granulated mixture together with theactive ingredient(s) and optionally one or more additionalpharmaceutically acceptable excipients. Thus, the binder may besuspended or dissolved in a suitable granulation liquid, which is thensprayed onto the powdery mixture of the active ingredient(s). Given thebinder is used for the preparation of granulated matter the binder ispreferably selected from unmodified starch, maltodextrin, hydroxypropylcellulose and hydroxypropyl methylcellulose.

Thus, it should be understood that a binder, in some embodiments of theinvention, is present in the internal phase only, i.e. internally and/oron the surface of the granulated form of the active ingredient(s). Inother embodiments of the invention, the binder is present in theexternal phase, i.e. only outside the granules. In still otherembodiments of the invention, the binder is present in the internalphase as well as in the external phase.

The dosage form of the invention may contain a super disintegrants.However, it is currently believed that the addition of superdisintegrants is not necessary due to the favourable disintegrationcharacteristics of the dosage form according to the invention. Specificexamples of super disintegrants include sodium starch glycolate,croscarmellose and crosslinked PVP. Accordingly, in a preferredembodiment, the dosage form of the invention does not contain a superdisintegrant.

The term “disintegrant” is meant to define an agent ensuring thedisintegration process whereby an dosage form breaks up into fragmentsand particles, exposing a large surface area of the active ingredient(s)to the gastric fluid and thus allowing dissolution to occur morerapidly. Typical examples of “normal” disintegrants are agar; alginicacid; alginates; bentonit; veegum; cellulose derivatives, such ascarboxymethyl cellulose sodium; gelatine; pectines; polymethacrylic acidderivatives of starch; unmodified, modified as well as partiallymodified starch; polymeric sugar derivatives, such as soyapolysaccharides; polymeric cyclodextrin; and xylan. A disintegrant maybe present in the internal or external phase. In an interestingembodiment of the invention, the disintegrant is starch, such as amixture of unmodified starch and modified starch.

Additional examples of further excipients, which may be included in thedosage form of the invention, include fillers (sugars, such as lactose,sucrose, dextrose and dextrates; sugar alcohols, such as mannitol,sorbitol and xylitol; carbonates and phosphates of alkaline earthmetals, such as calcium carbonate and calcium phosphate; celluloses,such as powdered cellulose and microcrystalline cellulose; colloidalsilica; titanium dioxide; kaolin; talc), and lubricants (such asmagnesium stearate).

Given that the dosage form is preferably in the form of a tablet, anadditional critical parameter to be considered in order to provide rapiddisintegration is the tablet hardness. The compressed tablet may exhibitsufficient hardness so as to resist physical stress during packaging,transport and application. On the other hand, the hardness should allowfor rapid disintegration of the tablet. Thus, in one embodiment of theinvention, a hardening agent is added.

In the present context, the term “hardening agent” means an excipientthat is incorporated into a compressed tablet composition to impartincreased hardness thereto. Exemplary hardening agents include calciumcarbonate; di- and tri-calcium phosphate; calcium sulfate;microcrystalline cellulose; powdered cellulose; dextrates; dextrin;sugars, such as dextrose, fructose, lactose, mannitol, sorbitol andsucrose; glyceryl palmitostearate; kaolin; magnesium carbonate;magnesium oxide; maltodextrin; potassium chloride, sodium chloride;starch; pregelatinized starch; talc and hydrogenated vegetable oil. In apreferred embodiment, the hardening agent is modified starch.

“Hardness” of a tablet is measured as the force in N (Newton) requiredto break a tablet. In an interesting embodiment, the tablet of theinvention has a hardness in the range of from 25N to 120N, preferably inthe range of from 35N to 90N, most preferably in the range of from 40Nto 80N, corresponding to a round-shaped tablet core of about 80 mg inweight. It is well known within the skilled artisan to define suitablehardness ranges depending on the size and the shape of the tablets.

In a preferred embodiment, the tablet core is provided with a film-coatfor the ease of swallowing the tablet. The film-coating may containfilm-coating agents such as hydroxypropylmethyl cellulose, macrogol,talc, and colouring agents such as titanium dioxide, ferric oxidepigment yellow.

Since the dosage form is preferably provided as an immediate releasedosage form, it is preferred that the dosage form does not contain agastric resistant film coat (enteric film coat)

The phrase “granulated form” indicates that the resulting physical form,when a powdery mixture of an active ingredient(s) and one or moreexcipients is transformed into partly agglomerated particles and/orgranules, has a particle size larger than the unprocessed powderymixture. The transformation may take place using any suitable apparatusknown to the skilled person, preferably by contacting the powderymixture with a granulation liquid using suitable granulation equipment,such as fluidised bed granulation.

By the term “granulating” is understood a mechanical process whereby apowder comprising the active component and excipients are partlyagglomerated into particles and/or granules having a larger particlesize than the unprocessed powder. In one embodiment, the powdery mixtureof DRSP and E2 and excipients is contacted with a granulation liquid,which may comprise the binder, swelled, partly dissolved or completelydissolved in the granulation liquid. The granulation liquid may be anysuitable solvent, but generally aqueous solutions or just water areapplicable. In one embodiment, the powdery mixture is contacted with thegranulation liquid using suitable equipment for wet-granulation, such asfluidised bed equipment. Furthermore, high shear granulation can be usedinstead of fluidised bed granulation.

In another suitable embodiment of the invention, the granulation liquiddoes not contain the binder. The binder is then added in dry form to thepowdery mixture of the DRSP and the E2 concurrently with a granulationliquid.

As indicated supra, another aspect of the present invention is directedto a packaging unit consisting of a number of separately packaged andindividually removable solid oral dosage forms as according to theinvention, and intended for oral administration for a period of at least21 days. Such a packaging unit may be prepared in a manner analogous tothat of making oral contraceptives, and may, for example, be aconventional blister pack or any other form known for this purpose, suchas a pack containing the appropriate number of dosage units in a sealedblister pack with a cardboard, paperboard, foil plastic backing andenclosed in a suitable cover. Each blister pack may be numbered orotherwise marked. In a preferred embodiment of the invention the oraladministration is intended for 28 days, i.e. the blister pack in thiscase contains 28 separately packaged and individually removable dosageforms. Evidently, the number of dosage forms in this case is 28 or amultiple of 28, such as a 2 to 12 multiple 28, e.g. a 2 to 6 multiple of28.

The invention is further illustrated by the following non-limitingexamples.

EXAMPLES Example 1 Clinical Study

Study Design

The clinical study was a multicenter, double-blind, randomized,placebo-controlled study to determine the lowest effective dose oforally administered E2 for the relief of moderate to severe vasomotorsymptoms in postmenopausal women over a treatment period of 12 weeks.

The Placebo Group received daily a tablet containing 0 mg E2 (and noDRSP) for 12 weeks.

The 1^(st) Treatment Group received daily a tablet containing 0.3 mg E2(and no DRSP) for 12 weeks.

The 2^(nd) Treatment Group received daily a tablet containing 0.5 mg E2and 0.25 mg DRSP for 12 weeks.

All three groups had comparable mean and median values at baseline withrespect to the frequency of moderate to severe hot flushes.

Efficacy

The below table shows the proportion of responders by treatment group:

Placebo 1^(st) Treatment Group 2^(nd) Treatment Group Parameter Group(0.3 mg E2) (0.5 mg E2/0.25 mg DRSP) Number of 176 (100%)  170 (100%)  177 (100%)  subjects Responder: No 129 (73.3%) 91 (50.8%)  66 (37.3%)Yes  47 (26.7%) 88 (49.2%) 111 (62.7%) p-value¹⁾ <0.0001 <0.0001¹⁾p-values were determined by Fisher's exact test comparing theTreatment Group in question with the Placebo Group

Without further elaboration, it is believed that one skilled in the artcan, using the preceding description, utilize the present invention toits fullest extent. The preceding preferred specific embodiments are,therefore, to be construed as merely illustrative, and not imitative ofthe remainder of the disclosure in any way whatsoever.

In the foregoing and in the examples, all temperatures are set forthuncorrected in degrees Celsius and, all parts and percentages are byweight, unless otherwise indicated.

The entire disclosures of all applications, patents and publications,cited herein and of corresponding European application No. 10160072.4,filed Apr. 15, 2010, are incorporated by reference herein.

The preceding examples can be repeated with similar success bysubstituting the generically or specifically described reactants and/oroperating conditions of this invention for those used in the precedingexamples.

From the foregoing description, one skilled in the art can easilyascertain the essential characteristics of this invention and, withoutdeparting from the spirit and scope thereof, can make various changesand modifications of the invention to adapt it to various usages andconditions.

What is claimed is:
 1. A method for preventing, treating or alleviatingvasomotor symptoms in a woman, said method comprising administering a asolid oral dosage form comprising about 0.5 mg estradiol and about 0.25mg drospirenone, and at least one pharmaceutically acceptable excipient.2. The method according to claim 1, wherein said vasomotor symptoms arehot flushes.
 3. The method according to claim 1, wherein said dosageform is a tablet.
 4. The method according to claim 1, wherein saidestradiol is in the form of estradiol hemihydrate.
 5. The methodaccording to claim 1, wherein said estradiol is in the form of apharmaceutically acceptable ester of estradiol.
 6. The method accordingto claim 1, wherein said woman is a postmenopausal woman.
 7. A methodfor lowering the frequency of breakthrough bleedings, or increasing theincidence rate of amenorrhea, in a woman, said method comprisingadministering a solid oral dosage form comprising about 0.5 mg estradioland about 0.25 mg drospirenone, and at least one pharmaceuticallyacceptable excipient.
 8. The method according to claim 7, wherein saiddosage form is a tablet.
 9. The method according to claim 7, whereinsaid estradiol is in the form of estradiol hemihydrate.
 10. The methodaccording to claim 7, wherein said estradiol is in the form of apharmaceutically acceptable ester of estradiol.
 11. The method accordingto claim 7, wherein said woman is a postmenopausal woman.